Since the discovery that 3'-azido-3'-deoxythymidine (AZT) is therapeutically useful in the treatment of AIDS, there has been a tremendous rebirth of interest in the preparation of modified nucleosides. At this time the only recognized clinical treatments for HIV infections involve use of nucleoside analogues. At the same time, the limitations of these drugs spur efforts to identify both superior pharmaceutical agents and new types of therapy such as those based on oligonucleotide mimics. The possibility of rational drug design through preparation of antisense oligonucleotides is an appealing new approach to antiviral agents, but more facile access to stable analogues of natural nucleotides, especially those that afford resistance to hydrolysis by nucleases, is badly needed. By developing the chemistry described in this proposal, we would: 1) generate several new families of potential antiviral agents; 2) foster efforts to separate the antiviral activity of nucleoside analogues from their cytotoxicity by opening nucleoside chemistry to more reactions traditional in natural products synthesis; and, 3) develop routes to stable analogues of dinucleotides that would be of interest for incorporation in antisense oligonucleotides. For some time, we have studied new methods for phosphonate synthesis, especially preparation of beta-keto phosphonates. These compounds display a pattern of functionality that results in extraordinary versatility as synthetic intermediates, and we have used them for synthesis of complex natural products. More recently we have begun to focus on preparation of nucleoside phosphonates, compounds that could have both significant versatility as synthetic intermediates and biological activity as antiviral agents. In the next phase of this program, we propose to: l) study the chemistry of compounds we refer to as "endo-modified" nucleosides, primarily 3'- phosphono nucleosides; 2) develop the chemistry of compounds we refer to as "exo-modified" nucleosides, primarily 3'-modified compounds with varied functionality at the 2'-position; and, 3) explore the preparation and activity of several unique dinucleotide analogues that may be capable of inhibiting nuclease activity.